Unexplained collapse of cardiac and respiratory rhythmicity is a final common mechanism for SUDEP, a major and preventable cause of death in persons with epilepsy. Recent evidence shows that dysfunctional ion channels and receptors co-expressed in brain, autonomic, heart, and respiratory pathways, along with clinical measures of functional disturbances in these pathways at times surrounding seizures represent detectable and potentially treatable risk factors for SUDEP. This proposal describes an integrated multicenter and multidisciplinary collaborative project that will combine a basic science, human neurogenetics, and clinical physiology approaches to these biological risk factors in a bench to bedside translational research program to identify, validate, and clinically evaluate predictive biomarkers and preventative treatments for SUDEP. The SUDEP Center Research Pipeline will consist of a serially interrelated work flow among 6 investigators in the center. Project 1 (Baylor) will expand the repository of DNA samples from patient at 3 centers (EMU, Dravet Syndrome Clinic, SUDEP DNA Repository) and other national networks which will be analyzed using chip microarrays for >247 prioritized ion channel and receptor genes mediating cardiac arrhythmias, respiratory depression and epilepsy. Projects 2-4 (Baylor U. Michigan, U. Iowa) analyze the biology, physiology, and pharmacology of these and related gene mutations at the cellular and in vivo level in SUDEP mouse models and induced pluripotent stem cells from Dravet Syndrome cases in order to understand and validate the SUDEP phenotypes. Project 5 (U.C. Davis/Childrens Memorial Chicago) will refine clinical respiratory and cardiac biomarkers obtained during epilepsy monitoring of individuals with Dravet Syndrome and others at high risk of sudden death (ictal hypoxemia, cardiac arrhythmia). Once validated, genes from these cases are added to an incremental diagnostic chip in development at Baylor for routine patient risk assessment in clinics in individuals with other clinical biomarkers.